JP6088044B2 - Composition for preventing muscle aging - Google Patents
Composition for preventing muscle aging Download PDFInfo
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- JP6088044B2 JP6088044B2 JP2015510016A JP2015510016A JP6088044B2 JP 6088044 B2 JP6088044 B2 JP 6088044B2 JP 2015510016 A JP2015510016 A JP 2015510016A JP 2015510016 A JP2015510016 A JP 2015510016A JP 6088044 B2 JP6088044 B2 JP 6088044B2
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- aging
- oxcart
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Description
本発明は、筋の老化防止用組成物に関するものである。 The present invention relates to a composition for preventing muscle aging.
近年、加齢に伴う筋力の低下および筋肉量の減少を「サルコペニア」とよび、寝たきりに関与するものとして非常に注目されている。サルコペニアには加齢に伴って変化する身体活動の低下の他、栄養摂取量、ホルモン、炎症反応など様々な要因が関与すると言われており、80歳以上では50%以上が罹患していると推計される。サルコペニアが生じると、易転倒・転落、骨折、体動制限そしてサルコペニアの進行という悪循環を呈し、寝たきり状態を誘発する。70歳以上でサルコペニアを合併している場合、合併していない場合と比べて死亡率は2.3倍になるという報告もある。厚生白書によると、日本では2025年には寝たきりの高齢者が230万人に達すると推計されており、サルコペニアの予防や治療は重要な課題である。 In recent years, a decrease in muscle strength and a decrease in muscle mass associated with aging is called “sarcopenia” and has attracted much attention as being related to bedridden. It is said that sarcopenia is associated with various factors such as nutritional intake, hormones, and inflammatory response in addition to the decline in physical activity that changes with age. Estimated. When sarcopenia occurs, it causes a vicious circle of easy falls / falls, fractures, body movement limitations, and progression of sarcopenia, and induces a bedridden state. There is a report that mortality rate is 2.3 times higher when sarcopenia is merged at the age of 70 or more than when not merging. According to the welfare white paper, it is estimated that the number of bedridden elderly people will reach 2.3 million in 2025 in Japan, and prevention and treatment of sarcopenia is an important issue.
現在、サルコペニアの予防および治療において、最も有効な手段は筋力トレーニングであるが(非特許文献1、2)、関節や循環器などの合併症を持つ高齢者や、既に体動制限を余儀なくされたりしている高齢者に対して、必要十分な強度の運動介入は困難である。サルコペニアの予防および治療薬として、必須アミノ酸、ホルモン剤(テストステロン、エストロゲン、成長ホルモン)、ACE阻害剤の臨床研究がなされているが、アミノ酸は治療効果がなく(非特許文献3)、ホルモン剤は乳がんや前立腺がん等のリスクが上がり、ACE阻害剤は症例が少なくエビデンス構築に至らないと報告されている(非特許文献4)。つまり、現在のところサルコペニアに対して十分な対策が行われていない状況であり、その治療薬として承認されている薬剤は皆無である。 Currently, muscle training is the most effective means for prevention and treatment of sarcopenia (Non-patent Documents 1 and 2), but elderly people with complications such as joints and circulatory organs, and body movement restrictions have already been forced. It is difficult for the elderly who are engaged in exercise intervention with sufficient and sufficient intensity. As a prophylactic and therapeutic agent for sarcopenia, clinical studies have been conducted on essential amino acids, hormone agents (testosterone, estrogen, growth hormone), and ACE inhibitors, but amino acids have no therapeutic effect (Non-patent Document 3). It has been reported that the risk of breast cancer, prostate cancer, etc. is increased, and ACE inhibitors have few cases and do not lead to evidence construction (Non-patent Document 4). In other words, at present, sufficient measures have not been taken against sarcopenia, and there is no drug approved as a therapeutic drug.
本発明は、筋の老化防止に有用な組成物、特に老化に伴う筋の委縮を改善することによりサルコペニアの予防または改善に有用な組成物を提供することを課題とする。 It is an object of the present invention to provide a composition useful for preventing muscle aging, particularly a composition useful for preventing or improving sarcopenia by improving muscle atrophy associated with aging.
本発明は、上記課題を解決するために、以下の各発明を包含する。
[1]ジオウの含有成分、サンシュユの含有成分、サンヤクの含有成分、タクシャの含有成分、ブクリョウの含有成分、ボタンピの含有成分、ケイヒの含有成分、ブシの含有成分、ゴシツの含有成分およびシャゼンシの含有成分からなる群より選択される一種または二種以上の成分を含有することを特徴とする筋の老化防止用組成物。
[2]ジオウの含有成分、ボタンピの含有成分、ケイヒの含有成分、ブシの含有成分、ゴシツの含有成分およびシャゼンシの含有成分からなる群より選択される一種または二種以上の成分を含有することを特徴とする前記[1]に記載の組成物。
[3]ジオウ、サンシュユ、サンヤク、タクシャ、ブクリョウ、ボタンピ、ケイヒ、ブシ、ゴシツおよびシャゼンシからなる群より選択される一種または二種以上の生薬を含有することを特徴とする前記[1]に記載の組成物。
[4]ジオウ、ボタンピ、ケイヒ、ブシ、ゴシツおよびシャゼンシからなる群より選択される一種または二種以上の生薬を含有することを特徴とする前記[3]に記載の組成物。
[5]筋の萎縮を改善する前記[1]〜[4]のいずれかに記載の組成物。
[6]サルコペニアの予防および/または改善用である前記[1]〜[5]のいずれかに記載の組成物。
[7]前記[1]〜[6]のいずれかに記載の組成物を含有する医薬。
[8]前記[1]〜[6]のいずれかに記載の組成物を含有する飲食品。
[9]前記[1]〜[6]のいずれかに記載の組成物を含有するサプリメント。
[10]牛車腎気丸、八味丸または六味丸である前記[7]に記載の医薬。The present invention includes the following inventions in order to solve the above problems.
[1] Giant-containing component, Sanshuyu-containing component, Sanyaku-containing component, Takusha-containing component, Bukuryu-containing component, Boppi-containing component, Keihi-containing component, Bushi-containing component, Goshitsu-containing component A composition for preventing muscle aging, comprising one or more components selected from the group consisting of components.
[2] Containing one or two or more kinds of components selected from the group consisting of an ingredient containing rainbow, a button pi, a cinnamon, a bush, a gossip and a shazenshi The composition as described in [1] above,
[3] The method according to [1] above, which comprises one or two or more herbal medicines selected from the group consisting of Ziou, Sangshuyu, Sanyaku, Takusha, Bukkyou, Buttonpi, Keihi, Bushi, Goshitsu and Shazenshi. Composition.
[4] The composition as described in [3] above, which contains one or more herbal medicines selected from the group consisting of Ziou, Buttonpi, Keihi, Bushi, Goshitsu and Shazenshi.
[5] The composition according to any one of [1] to [4], which improves muscle atrophy.
[6] The composition according to any one of [1] to [5], which is used for prevention and / or improvement of sarcopenia.
[7] A medicament comprising the composition according to any one of [1] to [6].
[8] A food and drink containing the composition according to any one of [1] to [6].
[9] A supplement containing the composition according to any one of [1] to [6].
[10] The medicine according to [7] above, which is Oxshajinkimaru, Hachimimaru or Rokumimaru.
本発明により、筋の老化防止に有用な組成物を提供することができる。本発明の組成物は、老化に伴う筋の委縮を改善することができ、サルコペニアの予防または改善用の医薬、飲食品、サプリメント等として非常に有用である。 According to the present invention, a composition useful for preventing muscle aging can be provided. The composition of the present invention can improve muscle atrophy associated with aging, and is very useful as a medicine, food or drink, supplement or the like for preventing or improving sarcopenia.
漢方では、生長・発育・生殖をつかさどる生命エネルギーを腎気と呼び、腎気が加齢によって減少した状態を腎虚と呼ぶ。腎虚になると、関節痛、下肢のしびれ、耳鳴り、夜間の頻尿などのいわゆる老化の症状を示す。腎虚の諸症状を改善する漢方薬は補腎剤と呼ばれ、牛車腎気丸、八味丸(八味地黄丸、八味腎気丸とも称される)、六味丸(六味地黄丸とも称される)などが知られている。 In Kampo, the vital energy that governs growth, development, and reproduction is called nephrophysis, and the state in which nephrophysis decreases with age is called nephrosis. When the kidney is collapsed, it shows symptoms of aging such as joint pain, numbness of the lower limbs, tinnitus, and frequent urination at night. Kampo medicines that improve various symptoms of renal dysfunction are called prosthetics, oxcart nephrology, Hachimimaru (also known as Hachimi-jio-maru, Hachimi-ken-kimaru), Rokumi-maru (also known as six-flavored yellow circle) ) Etc. are known.
牛車腎気丸は、疲れやすい、四肢が冷えやすい、尿量減少または多尿、口渇等の症状を伴う下肢痛、腰痛、しびれ、老人のかすみ目、かゆみ、排尿困難、頻尿、むくみ等に効果がある。八味丸は、疲労・倦怠感、尿量減少または多尿、口渇、手足に交互に冷感と熱感がある等の症状を伴う腎炎、糖尿病、陰萎、坐骨神経痛、腰痛、脚気、膀胱カタル、前立腺肥大、高血圧等に効果がある。六味丸は、疲れやすい、尿量減少または多尿、口渇等の症状を伴う排尿困難、頻尿、むくみ、かゆみ等に効果がある。しかし、これらの補腎剤が加齢に伴う筋力の低下や筋肉量の減少にどのような効果を奏するかについては知られていない。本発明者は、補腎剤と呼ばれる漢方薬の成分が老化による筋の委縮を改善することを見出し、本発明を完成した。 Oxshajinkigan is easy to get tired, limbs tend to cool down, lower limb pain with low urine volume or polyuria, dry mouth, low back pain, numbness, blurred vision of the elderly, itching, difficulty in urination, frequent urination, swelling, etc. effective. Hachimi-maru has fatigue / malaise, decreased urine output or polyuria, dry mouth, nephritis with symptoms such as alternating cold and hot feelings in the limbs, diabetes, negative wisdom, sciatica, low back pain, beriberi, bladder Effective for catarrh, prostate enlargement, hypertension, etc. Rokumimaru is effective for fatigue, urine loss or polyuria, difficulty in urination with symptoms such as dry mouth, frequent urination, swelling and itching. However, it is not known what effect these renal supplements have on muscular strength reduction and muscle mass reduction with aging. The present inventor has found that a component of a Chinese medicine called a renal replacement agent improves muscle atrophy due to aging, and has completed the present invention.
本発明は、ジオウの含有成分、サンシュユの含有成分、サンヤクの含有成分、タクシャの含有成分、ブクリョウの含有成分、ボタンピの含有成分、ケイヒの含有成分、ブシの含有成分、ゴシツの含有成分およびシャゼンシの含有成分からなる群より選択される一種または二種以上の成分を含有する筋の老化防止用組成物を提供する。 The present invention includes: Ziou-containing component, Sanshuyu-containing component, Sanyaku-containing component, Takusha-containing component, Bukuryo-containing component, Boppi-containing component, Keihi-containing component, Bushi-containing component, Goshitsu-containing component, and Shazenshi-shi. There is provided a composition for preventing muscle aging containing one or more components selected from the group consisting of:
ジオウ(地黄)はゴマノハグサ科ジオウ属植物の根茎である。ジオウの含有成分としては、カタルポール等のイリドイド配糖体、マンニノトリオース、ラフィノース、スタキオース等の糖類、マンニトール等の糖アルコール、アルギニン等のアミノ酸、リン酸類などが挙げられる。
サンシュユ(山茱萸)は、ミズキ科サンシュユの種子を除いた果実を乾燥したものである。サンシュユの含有成分としては、モロニサイド、ロガニン、スウェロサイド等のイリドイド配糖体、没食子酸、リンゴ酸などが挙げられる。
サンヤク(山薬)は、ヤマノイモ科ヤマノイモの皮を薄く剥いて乾燥したものである。サンヤクの含有成分としては、デンプン、糖蛋白質、アミノ酸、コリン、アラントイン、ジアスターゼ、カタラーゼ、ムチンなどが挙げられる。
タクシャ(沢瀉)はオモダカ科サジオモダカの根茎を乾燥したものである。タクシャの含有成分としては、四環性トリテルペノイドのアリソールA、B、C、それらのアセチル化合物などが挙げられる。Jiou (jio) is a rhizome of the genus Dinoceae. Examples of the components contained in diau include iridoid glycosides such as catalpol, saccharides such as manninotriose, raffinose and stachyose, sugar alcohols such as mannitol, amino acids such as arginine, and phosphates.
Sanshuyu is a dried version of the fruit except for the seeds of Sanshuyu. Examples of components contained in sanshuyu include iridoid glycosides such as moloniside, loganin, and sweroside, gallic acid, malic acid, and the like.
Sanyak (Yakuyaku) is made by thinly peeling the skin of the Yam yam, and drying it. Examples of components contained in sanjak include starch, glycoprotein, amino acid, choline, allantoin, diastase, catalase, and mucin.
Takusha is a dried rhizome of the scorpionidae. Examples of the components containing the takusha include tetracyclic triterpenoids alisol A, B, C, and acetyl compounds thereof.
ブクリョウ(茯苓)は、サルノコシカケ科のマツホド菌の菌核を乾燥し外皮を除いたものである。ブクリョウの含有成分としては、パキマン等の多糖類、パキマ酸、エブリコ酸、デハイドロエブリコ酸、ツムロース酸等の四環性トリテルペンカルボン酸、エルゴステロールなどが挙げられる。
ボタンピ(牡丹皮)は、ボタン科ボタンの根の皮を乾燥したものである。ボタンピの含有成分としては、ペオニフロリン、ペオノール、ペオノサイド、ペオノライド、安息香酸、ベンゾイルオキシペオニフロリン、カンペステロールなどが挙げられる。
ケイヒ(桂皮)は、クスノキ科、ニッケイの樹皮、または周皮の一部を除いたものである。ケイヒの含有成分としては、精油、ケイヒアルデヒド、ジテルペノイド、カテキン類、タンニンなどが挙げられる。Bukryo (茯苓) is a dried nuclei of the pine fungus of the family Sarnococcidae, with the hull removed. Examples of the components contained in Bukuryo include polysaccharides such as pachyman, tetracyclic triterpene carboxylic acids such as pachymic acid, evericoic acid, dehydroebricic acid, and tumulonic acid, and ergosterol.
Buttonpi (peony skin) is a dried root skin of a button family button. Examples of the component containing buttonpi include paeoniflorin, peonol, peonoside, peonolide, benzoic acid, benzoyloxypeoniflorin, campesterol and the like.
Keihi (cinnamon bark) is obtained by removing a part of the camphor family, Nikkei bark, or pericytes. Examples of the ingredients contained in cinnamon include essential oil, cinnaaldehyde, diterpenoids, catechins, and tannins.
ブシ(附子)は、キンポウゲ科トリカブトの塊根を減毒加工したものである。ブシの含有成分としては、強毒性のブシジエステルアルカロイドとしてアコニチン、ジェサコニチン、ヒバコニチン、メサコニチン、低毒性のアチシン系としてアチシン、コブシン、イグナビン、ソンゴリン、強心成分としてハイゲナミン、コリネインなどが挙げられる。
ゴシツ(牛膝)は、ヒユ科ヒナタイノコズチまたはトウイノコズチの根である。ゴシツの含有成分としては、オレアノン酸、エクジソン、イノコステロンなどが挙げられる。
シャゼンシ(車前子)は、オオバコ科オオバコの種子である。シャゼンシの含有成分としてはイリドイド、粘液性多糖であるプランタサン、プランタゴームシラーゲA、フラバノン配糖体であるプランタゴシドなどが挙げられる。Bushi (Appendix) is a processed detoxified tuberous root of buttercupaceae aconite. Examples of the components contained in the bushes include aconitine, jessaconitine, hibaconitine, mesaconitine as highly toxic bushidiester alkaloids, assine, cobucin, ignabin, and songoline as low toxicity catechols, and hygenamine, corynein as the cardiac component.
Goshitsu (cow knee) is the root of the Amaranthaceae Hinata Taiko Kochi or Touinoko Kochi. Examples of the component containing gossip include oleanoic acid, ecdysone, and inocosterone.
Shazenshi is a seed of the plantain plantain. Examples of the components contained in shazenshi include iridoids, plantasan which is a mucous polysaccharide, planta goum silage A, and plantagoside which is a flavanone glycoside.
本発明の組成物は、ジオウの含有成分、ボタンピの含有成分、ケイヒの含有成分、ブシの含有成分、ゴシツの含有成分およびシャゼンシの含有成分からなる群より選択される一種または二種以上の成分を含有することが好ましく、ケイヒの含有成分、ブシの含有成分、ゴシツの含有成分およびシャゼンシの含有成分からなる群より選択される一種または二種以上の成分を含有することがより好ましい。 The composition of the present invention is one or two or more components selected from the group consisting of a component containing zioli, a component containing buttonpi, a component containing cinnamon, a component containing bushi, a component containing gohitsu and a component containing shazenshi It is preferable to contain 1 type, or 2 or more types of components selected from the group which consists of a cinnamon-containing component, a bushy-containing component, a gourd-containing component, and a shazenshi-containing component.
本発明の組成物は、ジオウ、サンシュユ、サンヤク、タクシャ、ブクリョウ、ボタンピ、ケイヒ、ブシ、ゴシツおよびシャゼンシからなる群より選択される一種または二種以上の生薬を含有するものであってもよい。本発明の組成物は、ジオウ、ボタンピ、ケイヒ、ブシ、ゴシツおよびシャゼンシからなる群より選択される一種または二種以上の生薬を含有することが好ましく、ケイヒ、ブシ、ゴシツおよびシャゼンシからなる群より選択される一種または二種以上の生薬を含有することがより好ましい。 The composition of the present invention may contain one or two or more kinds of herbal medicines selected from the group consisting of Diou, Sanshuyu, Sanyaku, Takusha, Bukkuri, Buttonpi, Keihi, Bushi, Goshitsu, and Shazenshi. The composition of the present invention preferably contains one or two or more kinds of herbal medicines selected from the group consisting of Dianthus, Buttonpi, Keihi, Bushi, Gosh and Shazenshi, and from the group consisting of Keihi, Bushi, Gosh and Shazenshi It is more preferable to contain one or more selected herbal medicines.
生薬は生薬の粉砕物または生薬の抽出エキスであることが好ましい。生薬の抽出エキスは、例えば原料生薬を単独または混合し、生薬の合計質量に対して約5〜約25倍量の水を加えて、通常約80〜約100℃で約30分間〜約2時間加熱してエキスを煎出し、濾過等を行って固形成分を除去することにより製造することができる。得られた抽出エキスを、例えばスプレードライ、減圧濃縮乾燥、凍結乾燥等により乾燥し、乾燥エキス粉末としてもよい。 The herbal medicine is preferably a herbal pulverized product or a herbal extract. The extract of herbal medicine is, for example, raw herbal medicine alone or mixed, and about 5 to about 25 times the amount of water is added to the total mass of the herbal medicine, usually at about 80 to about 100 ° C. for about 30 minutes to about 2 hours. The extract can be brewed by heating, and the solid component can be removed by filtration or the like. The obtained extract may be dried by, for example, spray drying, vacuum concentration drying, freeze drying, or the like to obtain a dry extract powder.
本発明の組成物は、筋の老化を有効に防止することができる。特に、老化に伴う筋の委縮を顕著に改善することができるので、サルコペニア(加齢に伴う筋力の低下および筋肉量の減少)の予防および/または改善用の組成物としてとして非常に有用である。本発明の組成物は、医薬、飲食品、サプリメント、食品添加物、飼料、飼料添加物等の形態で実施することができる。本発明の組成物に含有される生薬またはその含有成分は、漢方薬として広く使用されているので、ヒトや他の哺乳動物(例えば、ラット、マウス、ウサギ、ヒツジ、ブタ、ウシ、ネコ、イヌ、サルなど)に対して、安全に長期間摂取させることができる。 The composition of the present invention can effectively prevent muscle aging. In particular, muscle atrophy associated with aging can be remarkably improved, and thus it is very useful as a composition for preventing and / or improving sarcopenia (decreased muscle strength and muscle mass associated with aging). . The composition of this invention can be implemented with forms, such as a pharmaceutical, food-drinks, a supplement, a food additive, a feed, a feed additive. Since the herbal medicine or its component contained in the composition of the present invention is widely used as a traditional Chinese medicine, humans and other mammals (for example, rats, mice, rabbits, sheep, pigs, cows, cats, dogs, Monkeys, etc.) can be safely ingested for a long time.
老化防止の対象となる筋は特に限定されないが、骨格筋が好ましい。骨格筋としては、例えば、胸鎖乳突筋、大胸筋、小胸筋、前鋸筋、鎖骨下筋、腹直筋、外腹斜筋、内腹斜筋、腹横筋、腰方形筋、僧帽筋、広背筋、脊柱起立筋、肩甲挙筋、菱形筋、三角筋、小円筋、棘上筋、棘下筋、肩甲下筋、大円筋、烏口腕筋、上腕二頭筋、上腕筋、腕橈骨筋、上腕三頭筋、肘筋、円回内筋、方形回内筋、回外筋、尺側手根屈筋、橈側手根屈筋、長掌筋、浅指屈筋、深指屈筋、長母指屈筋、長橈側手根伸筋、短橈側手根伸筋、尺側手根伸筋、指伸筋、示指伸筋、小指伸筋、長母指伸筋、短拇指伸筋、長母指外転筋、中様筋(4筋)、掌側骨間筋(3筋)、背側骨間筋(4筋)、小指外転筋、短小指屈筋、小指対立筋、短掌筋、母指内転筋、短拇指屈筋、母指対立筋、短拇指外転筋、大腿直筋、外側公筋、中間公筋、内側広筋、腸骨筋、大腰筋、小腰筋、縫工筋、恥骨筋、大腿筋膜張筋、大殿筋、大腿二頭筋、半腱様筋、半膜様筋、中殿筋、小殿筋、薄筋、長内転筋、短内転筋、大内転筋、深層外旋六筋、腓腹筋、ヒラメ筋、膝窩筋、後脛骨筋、長趾屈筋、長母趾屈筋、足底筋、前脛骨筋、長腓骨筋、短腓骨筋、第3腓骨筋、長母趾伸筋、長趾伸筋などが挙げられる。好ましくはヒラメ筋、大腿直筋、脊柱起立筋である。 The muscle that is subject to aging prevention is not particularly limited, but skeletal muscle is preferred. Examples of skeletal muscles include the sternocleidomastoid muscle, the great pectoral muscle, the small pectoral muscle, the anterior sawnous muscle, the subclavian muscle, the rectus abdominis muscle, the external oblique muscle, the internal oblique muscle, the transverse abdominal muscle, the lumbar muscle, the monk. Cap muscle, latissimus dorsi, spine standing muscle, levator scapula, rhomboid, triangular muscle, small circular muscle, supraspinatus, subspinous muscle, subscapular muscle, great circular muscle, incisor arm, biceps , Brachial muscles, brachial muscles, triceps, elbows, circular rotator muscles, rectangular rotator muscles, supination muscles, ulnar carpal flexors, radial carpal flexors, long palmar muscles, superficial finger flexors, deep Finger flexor, long thumb flexor, long lateral carpal extensor, short lateral carpal extensor, ulnar carpal extensor, finger extensor, index finger extensor, little finger extensor, long thumb extensor, short thumb extensor Muscles, long thumb abductors, medial muscles (4 muscles), palmar interosseous muscles (3 muscles), dorsal interosseous muscles (4 muscles), little finger abductor, short finger flexor, little finger allele, Short palmar muscle, thumb adductor, short flexor flexor, thumb allele, short finger abductor, rectus femoris, lateral common, intermediate common, medial broad , Iliac muscle, psoas muscle, psoas muscle, sewing muscle, pubic muscle, thigh fascia latae muscle, gluteal muscle, biceps femoris, semi-tendonoid muscle, semi-membranous muscle, mid gluteus Muscle, thin muscle, long adductor, short adductor, major adductor, deep external rotation 6 muscles, gastrocnemius, soleus, popliteal muscle, posterior tibialis, long flexor, long mother flexor, sole Examples include muscle, anterior tibial muscle, long peroneal muscle, short peroneal muscle, third peroneal muscle, long mother's extensor muscle, and long peroneal extensor muscle. Preferred are the soleus, rectus femoris, and spinal column erect muscles.
本発明は、上記本発明の組成物を含有する医薬を提供する。本発明の医薬は、筋の委縮改善用の医薬、サルコペニアの予防および/または改善(治療)用の医薬として好適である。本発明の医薬は、上記本発明の組成物に、薬学的に許容される担体、さらに添加剤を適宜配合して製剤化することができる。具体的には錠剤、被覆錠剤、丸剤、散剤、顆粒剤、カプセル剤、液剤、懸濁剤、乳剤等の経口剤;注射剤、輸液、坐剤、軟膏、パッチ剤等の非経口剤とすることができる。担体または添加剤の配合割合については、医薬品分野において通常採用されている範囲に基づいて適宜設定すればよい。配合できる担体または添加剤は特に制限されないが、例えば、水、生理食塩水、その他の水性溶媒、水性または油性基剤等の各種担体;賦形剤、結合剤、pH調整剤、崩壊剤、吸収促進剤、滑沢剤、着色剤、矯味剤、香料等の各種添加剤が挙げられる。 The present invention provides a medicament containing the composition of the present invention. The medicament of the present invention is suitable as a medicament for improving muscle atrophy and a medicament for preventing and / or improving (treating) sarcopenia. The medicament of the present invention can be formulated by appropriately blending a pharmaceutically acceptable carrier and an additive into the composition of the present invention. Specifically, oral preparations such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions; parenterals such as injections, infusions, suppositories, ointments, patches, etc. can do. What is necessary is just to set suitably about the mixture ratio of a carrier or an additive based on the range normally employ | adopted in the pharmaceutical field | area. Carriers or additives that can be blended are not particularly limited. For example, various carriers such as water, physiological saline, other aqueous solvents, aqueous or oily bases; excipients, binders, pH adjusters, disintegrants, absorption Various additives such as an accelerator, a lubricant, a colorant, a corrigent, and a fragrance are included.
錠剤、カプセル剤などに混和することができる添加剤としては、例えば、ゼラチン、コーンスターチ、トラガント、アラビアゴムのような結合剤、結晶性セルロースのような賦形剤、コーンスターチ、ゼラチン、アルギン酸などのような膨化剤、ステアリン酸マグネシウムのような潤滑剤、ショ糖、乳糖またはサッカリンのような甘味剤、ペパーミント、アカモノ油またはチェリーのような香味剤などが用いられる。調剤単位形態がカプセルである場合には、上記タイプの材料にさらに油脂のような液状担体を含有することができる。注射のための無菌組成物は通常の製剤手順(例えば有効成分を注射用水、天然植物油等の溶媒に溶解または懸濁させる等)に従って調製することができる。注射用の水性液としては、例えば、生理食塩水、ブドウ糖やその他の補助薬を含む等張液(例えば、D−ソルビトール、D−マンニトール、塩化ナトリウムなど)などが用いられ、適当な溶解補助剤、例えば、アルコール(例、エタノール)、ポリアルコール(例、プロピレングリコール、ポリエチレングリコール)、非イオン性界面活性剤(例、ポリソルベート80TM、HCO−50)などと併用してもよい。油性液としては、例えば、ゴマ油、大豆油などが用いられ、溶解補助剤である安息香酸ベンジル、ベンジルアルコールなどと併用してもよい。また、緩衝剤(例えば、リン酸塩緩衝液、酢酸ナトリウム緩衝液)、無痛化剤(例えば、塩化ベンザルコニウム、塩酸プロカインなど)、安定剤(例えば、ヒト血清アルブミン、ポリエチレングリコールなど)、保存剤(例えば、ベンジルアルコール、フェノールなど)、酸化防止剤などと配合してもよい。Additives that can be mixed into tablets, capsules and the like include binders such as gelatin, corn starch, tragacanth, gum arabic, excipients such as crystalline cellulose, corn starch, gelatin, alginic acid and the like. Leavening agents, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavorings such as peppermint, red oil and cherry. When the dispensing unit form is a capsule, a liquid carrier such as fats and oils can be further contained in the above type of material. A sterile composition for injection can be prepared according to a usual formulation procedure (for example, dissolving or suspending an active ingredient in a solvent such as water for injection or natural vegetable oil). As an aqueous solution for injection, for example, isotonic solutions (eg, D-sorbitol, D-mannitol, sodium chloride, etc.) containing physiological saline, glucose and other adjuvants are used. For example, alcohol (eg, ethanol), polyalcohol (eg, propylene glycol, polyethylene glycol), nonionic surfactant (eg, polysorbate 80 ™ , HCO-50) and the like may be used in combination. As the oily liquid, for example, sesame oil, soybean oil and the like are used, and they may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), storage You may mix | blend with an agent (for example, benzyl alcohol, phenol, etc.), antioxidant, etc.
本発明の医薬は、牛車腎気丸、八味丸または六味丸であることが好ましい。本発明の医薬の1日当たりの投与量は、筋の老化防止に有効な量であって副作用の少ない量であれば特に限定されない。本発明の組成物の1日当たりの投与量は、市販の牛車腎気丸、八味丸または六味丸の1日当たりの投与量に準じて設定することが好ましい。 It is preferable that the pharmaceutical of the present invention is Goshajinkigan, Hachimimaru or Rokumimaru. The daily dose of the medicament of the present invention is not particularly limited as long as it is an amount effective for preventing muscle aging and has few side effects. The daily dose of the composition of the present invention is preferably set in accordance with the daily dose of commercially available ox carriage Kikimaru, Hachimimaru or Rokumimaru.
牛車腎気丸は、例えば通常質量比で、ジオウ5.0、サンシュユ3.0、サンヤク3.0、タクシャ3.0、ブクリョウ3.0、ボタンピ3.0、ケイヒ(桂皮)1.0、ブシ(附子)1.0、ゴシツ(牛膝)3.0、シャゼンシ(車前子)3.0からなる混合生薬から得られる濃縮エキスまたは乾燥エキス粉末が挙げられる。牛車腎気丸は、市販の漢方製剤(例えば、株式会社ツムラの「ツムラ牛車腎気丸エキス顆粒(医療用)」など)を好適に用いることができる。 For example, the oxcart nekigan is usually in a mass ratio of Ziou 5.0, Sanshuyu 3.0, Sanyaku 3.0, Takusha 3.0, Bukuryo 3.0, Buttonpi 3.0, Keihi (cinnamon) 1.0, Examples thereof include concentrated extract or dry extract powder obtained from a mixed herbal medicine consisting of Bushi (bushi) 1.0, Goshtsu (cow knee) 3.0, and Shazenshi (car front child) 3.0. As the oxcart nephricle, commercially available Kampo preparations (for example, “Tsumura oxshakengan extract granule (for medical use)” manufactured by Tsumura Corporation) can be suitably used.
八味丸は、例えば通常質量比で、ジオウ6.0、サンシュユ3.0、サンヤク3.0、タクシャ3.0、ブクリョウ3.0、ボタンピ2.5、ケイヒ1.0、ブシ0.5からなる混合生薬から得られる濃縮エキスまたは乾燥エキス粉末が挙げられる。八味丸は、市販の漢方製剤(例えば、株式会社ツムラの「ツムラ八味地黄丸エキス顆粒(医療用)」など)を好適に用いることができる。 Hachimi-maru, for example, is usually in a mass ratio of Geo 6.0, Sanshuu 3.0, Sanyaku 3.0, Takusha 3.0, Bukuryo 3.0, Buttonpi 2.5, Keihi 1.0, Bushi 0.5. Concentrated extract or dry extract powder obtained from the mixed crude drug consisting of As for Hachimimaru, a commercially available Chinese medicine preparation (for example, “Tsumura Hachimi-jiomaru extract granule (for medical use)” manufactured by Tsumura Co., Ltd.) can be suitably used.
六味丸は、例えば通常質量比で、ジオウ5.0、サンシュユ3.0、サンヤク3.0、タクシャ3.0、ブクリョウ3.0、ボタンピ3.0からなる混合生薬から得られる濃縮エキスまたは乾燥エキス粉末が挙げられる。六味丸は、市販の漢方製剤(例えば、株式会社ツムラの「ツムラ六味丸エキス顆粒(医療用)」など)を好適に用いることができる。 Rokumimaru is, for example, a concentrated extract obtained from a mixed herbal medicine consisting of Dio 5.0, Sanshuu 3.0, Sanyaku 3.0, Takusha 3.0, Bukuryo 3.0, and Buttonpi 3.0 in a normal mass ratio. An extract powder is mentioned. As Rokumimaru, a commercially available Chinese medicine formulation (for example, “Tsumura Rokumimaru Extract Granule (for medical use)” manufactured by Tsumura Corporation) can be suitably used.
本発明は、上記本発明の組成物を含有する飲食品を提供する。本発明の飲食品は、筋の委縮改善用の飲食品、サルコペニアの予防および/または改善用の飲食品として好適である。飲食品には、健康食品、機能性食品、特定保健用食品、病者用食品等が含まれる。飲食品の形態は特に限定されない。例えば茶飲料、清涼飲料、炭酸飲料、栄養飲料、果実飲料、乳酸飲料等の飲料、そば、うどん、中華麺、即席麺等の麺類、飴、キャンディー、ガム、チョコレート、スナック菓子、ビスケット、ゼリー、ジャム、クリーム、焼き菓子、パン等の菓子およびパン類、かまぼこ、ハム、ソーセージ等の水産・畜産加工食品、加工乳、発酵乳等の乳製品、サラダ油、てんぷら油、マーガリン、マヨネーズ、ショートニング、ホイップクリーム、ドレッシング等の油脂および油脂加工食品、ソース、たれ等の調味料、カレー、シチュー、丼、お粥、雑炊等のレトルトパウチ食品、アイスクリーム、シャーベット、かき氷等の冷菓などを挙げることができる。 This invention provides the food / beverage products containing the composition of the said invention. The food / beverage products of the present invention are suitable as food / beverage products for improving muscle atrophy and food / beverage products for prevention and / or improvement of sarcopenia. Foods and drinks include health foods, functional foods, foods for specified health use, foods for the sick, and the like. The form of the food or drink is not particularly limited. For example, beverages such as tea beverages, soft drinks, carbonated beverages, nutritive beverages, fruit beverages, lactic acid beverages, buckwheat noodles, Chinese noodles, instant noodles and other noodles, rice cakes, candy, gum, chocolate, snacks, biscuits, jelly, jam , Cream, baked confectionery, confectionery such as bread, and fishery products such as kamaboko, ham, sausage, processed food, dairy products such as processed milk, fermented milk, salad oil, tempura oil, margarine, mayonnaise, shortening, whipped cream And fats and fat processed foods such as dressings, seasonings such as sauces and sauces, retort pouch foods such as curry, stew, rice cakes, rice cakes and miscellaneous foods, and frozen desserts such as ice cream, sherbet and shaved ice.
本発明は、上記本発明の組成物を含有するサプリメントを提供する。本発明のサプリメントは、筋の委縮改善用のサプリメント、サルコペニアの予防および/または改善用のサプリメントとして好適である。サプリメントは、例えば錠剤、顆粒剤、散剤、ドリンク剤等の形態で提供することができる。
さらに本発明は、上記本発明の組成物を含有する食品添加物、飼料、飼料添加物等としても好適に実施することができる。The present invention provides a supplement containing the composition of the present invention. The supplement of the present invention is suitable as a supplement for improving muscle atrophy and a supplement for preventing and / or improving sarcopenia. Supplements can be provided in the form of tablets, granules, powders, drinks, and the like.
Furthermore, the present invention can also be suitably implemented as a food additive, feed, feed additive or the like containing the composition of the present invention.
本発明には、以下の各発明が含まれる。
哺乳動物に対してジオウの含有成分、サンシュユの含有成分、サンヤクの含有成分、タクシャの含有成分、ブクリョウの含有成分、ボタンピの含有成分、ケイヒの含有成分、ブシの含有成分、ゴシツの含有成分およびシャゼンシの含有成分からなる群より選択される一種または二種以上の成分の有効量を投与することを特徴とする筋の老化防止方法。
筋の老化防止用組成物を製造するための、ジオウの含有成分、サンシュユの含有成分、サンヤクの含有成分、タクシャの含有成分、ブクリョウの含有成分、ボタンピの含有成分、ケイヒの含有成分、ブシの含有成分、ゴシツの含有成分およびシャゼンシの含有成分からなる群より選択される一種または二種以上の成分の使用。
筋の老化防止に使用するための、ジオウの含有成分、サンシュユの含有成分、サンヤクの含有成分、タクシャの含有成分、ブクリョウの含有成分、ボタンピの含有成分、ケイヒの含有成分、ブシの含有成分、ゴシツの含有成分およびシャゼンシの含有成分からなる群より選択される一種または二種以上の成分。The present invention includes the following inventions.
Ingredients for Ziou, Sansyuyu, Sanyaku, Takusha, Bukuryo, Boppi, Bakipi, Bushi, Goshitsu A method for preventing muscle aging, comprising administering an effective amount of one or more components selected from the group consisting of components containing chazenshi.
In order to produce a composition for preventing the aging of muscles, the components of jiou, sanshuyu, sanyaku, takusha, bukkyou, pipi, keihi, Use of 1 type, or 2 or more types of components selected from the group which consists of a containing component, a gossip containing component, and a shazenshi containing component.
For use in preventing the aging of muscles One or more components selected from the group consisting of a gossip-containing component and a shazenshi-containing component.
以下、実施例により本発明を詳細に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to these.
〔実施例1:老化促進モデルマウスの骨格筋に対する牛車腎気丸の効果〕
(1)使用動物
老化促進モデルマウスであるSAMP8(7週齢、雄)および正常老化マウスであるSAMR(7週齢、雄)を日本エスエルシーから入手し、1週間の馴化後に試験に供した。動物は12時間明暗周期を持つ特定の病原体フリーの条件下で飼育した。[Example 1: Effect of Goshajinkigan on skeletal muscle of senescence accelerated mouse model]
(1) Animals used SAMP8 (7 weeks old, male), an aging-promoting model mouse, and SAMR (7 weeks old, male), a normal aging mouse were obtained from Japan SLC and subjected to the test after acclimation for 1 week. . Animals were raised under certain pathogen-free conditions with a 12 hour light / dark cycle.
(2)実験方法
(2-1)飼育および投与
実験プロトコールと飼育条件は大阪大学動物実験委員会によって承認され、「実験動物の管理と使用のための国立衛生研究所・ガイド」に従って、実験を実施した。
SAMP8およびSAMRを、それぞれ普通食(MF、オリエンタル酵母工業株式会社)のみを与える群(普通食群、n=6)および普通食に4質量%の牛車腎気丸(ツムラ牛車腎気丸;株式会社ツムラ)を加えた混合食を与える群(牛車腎気丸群、n=6)の2群に分け、38週齢まで給餌を行った。給餌期間中2週間に1回、全てのマウスについて全身状態を観察した。13週齢〜14週齢時に1週間の食事摂取量を測定した。体重測定は、試験開始時(8週齢)および試験終了時(38週齢)に行った。(2) Experimental method (2-1) Breeding and administration The experimental protocol and breeding conditions were approved by the Osaka University Animal Experiment Committee, and the experiment was conducted in accordance with the “National Institute of Health Research and Guide for Laboratory Animal Care and Use”. Carried out.
SAMP8 and SAMR are each given a normal diet (MF, Oriental Yeast Co., Ltd.) only (ordinary diet group, n = 6) and 4% by weight of the regular diet of Ushizura Kigiri (Tsumura Uzumaki Nigiri; stock) Divided into 2 groups (group of oxcart kidney kirimaru, n = 6) to which a mixed diet was added with (Tsumura Co., Ltd.), and feeding was carried out until 38 weeks of age. The general condition of all mice was observed once every 2 weeks during the feeding period. One week's food intake was measured at 13 to 14 weeks of age. The body weight was measured at the start of the test (8 weeks of age) and at the end of the test (38 weeks of age).
(2-2)サンプル採取
38週齢時にマウスを安楽死させ、下肢(大腿骨および脛骨を含む)を摘出した。大腿骨および脛骨を組織標本作製に供した。また、ヒラメ筋および大腿直筋を摘出し、直ちに液体窒素で凍結させ、その後−80℃で保存した。凍結保存したヒラメ筋および大腿直筋は、後日融解し、ホモジナイズしてウエスタンブロッティングに供した。(2-2) Sample collection The mice were euthanized at 38 weeks of age, and the lower limbs (including the femur and tibia) were removed. The femur and tibia were subjected to tissue preparation. In addition, the soleus and rectus femoris were extracted, immediately frozen in liquid nitrogen, and then stored at -80 ° C. Cryopreserved soleus and rectus femoris were thawed at a later date, homogenized, and subjected to Western blotting.
(2-3)組織標本
ヒラメ筋を観察するために、定法に従い脛骨の組織標本を作製してヘマトキシリン・エオジン染色を施した。また、遅筋(トロポニンI陽性)および速筋(トロポニンT陽性)を染色するために、抗トロポニンI抗体(TrponinI Rabbit polyclonal Ab (Novus Biologicals))および抗トロポニンT抗体(TrponinT (TT-98) Mouse monoclonal Ab (Abbiotec))を用いて、定法に従い免疫染色を行った。さらに、筋肉中のグリコーゲンを染色するためにPAS染色(Periodic acid-Schiff stain)を行った。(2-3) Tissue specimen In order to observe the soleus muscle, a tibial tissue specimen was prepared according to a conventional method and stained with hematoxylin and eosin. In addition, anti-troponin I antibody (TrponinI Rabbit polyclonal Ab (Novus Biologicals)) and anti-troponin T antibody (TrponinT (TT-98) Mouse are used to stain slow muscle (troponin I positive) and fast muscle (troponin T positive). Monoclonal Ab (Abbiotec)) was used for immunostaining according to a conventional method. Further, PAS staining (Periodic acid-Schiff stain) was performed to stain glycogen in muscle.
(2-4)筋線維面積測定
ヒラメ筋のヘマトキシリン・エオジン染色標本を用いて、1標本当たり16か所の任意の領域を選択し、二次元画像解析ソフトWinROOF(三谷商事)を用いて筋線維面積を測定した。解析は、一元配置分散分析で行った。(2-4) Muscle fiber area measurement Using the hematoxylin / eosin-stained specimen of the soleus muscle, select any 16 areas per specimen and use the two-dimensional image analysis software WinROOF (Mitani Corporation) for muscle fibers. The area was measured. Analysis was performed by one-way analysis of variance.
(2-5)ウエスタンブロッティングによる筋肉中のトロポニンIおよびトロポニンT発現量の解析
凍結保存した筋肉を、RIPAバッファーにプロテアーゼ阻害薬のカクテル(ナカライテスク)を追加したものでホモジナイズした。4℃で14000回転×5分間遠心分離し、上清を採取した。BCAプロテインアッセイキット(Thermo Fisher Scientific Inc.)を使って、タンパク質の定量を行った。等量のたんぱく質を用い、95℃で5分間熱し、SDS−PAGEに供した。SDS−PAGEには、15%ポリアクリルアミドゲルを用いた。PVDF膜に転写後、抗トロポニンI抗体(TrponinI Rabbit polyclonal Ab (Novus Biologicals))および抗トロポニンT抗体(TrponinT (TT-98) Mouse monoclonal Ab (Abbiotec))を、それぞれ4000倍に希釈し、4℃で16時間インキュベーションし、ホースラディッシュペルオキシダーゼ標識二次抗体(GE Healthcare Bio-Sciences Corp.)を用い、イムノスターゼータ(和光純薬)を使い発色させ、RX−Uフィルム(フジフィルム)で撮影し、GT−X970で画像を取り込み、評価を行った。(2-5) Analysis of expression levels of troponin I and troponin T in muscle by Western blotting The cryopreserved muscle was homogenized with RIPA buffer supplemented with a protease inhibitor cocktail (Nacalai Tesque). Centrifugation was performed at 14,000 rpm for 5 minutes at 4 ° C., and the supernatant was collected. Protein quantification was performed using a BCA protein assay kit (Thermo Fisher Scientific Inc.). An equal amount of protein was used, heated at 95 ° C. for 5 minutes, and subjected to SDS-PAGE. A 15% polyacrylamide gel was used for SDS-PAGE. After transfer to PVDF membrane, anti-troponin I antibody (Trponin I Rabbit polyclonal Ab (Novus Biologicals)) and anti-troponin T antibody (Trponin T (TT-98) Mouse monoclonal Ab (Abbiotec)) were diluted 4000 times each and 4 ° C. Incubate for 16 hours, use horseradish peroxidase-labeled secondary antibody (GE Healthcare Bio-Sciences Corp.), develop color using immunostar zeta (Wako Pure Chemical Industries), and shoot with RX-U film (Fuji film), Images were captured with GT-X970 and evaluated.
(2-6)ウエスタンブロッティングによる筋肉中のPGC−1α発現量の解析
SDS−PAGEに12.5%ポリアクリルアミドゲルを用い、抗体として、PGC1-alpha (4C1.3) Mouse monoclonal Ab(Calbiochem, Billerica)を1000倍希釈で、GAPDH (14C10) Rabbit monoclonal Ab (Cell Signaling Technology)を10000倍希釈で、それぞれ用いたこと以外は、上記(2-5)と同様にウエスタンブロッティングを行った。(2-6) Analysis of PGC-1α expression level in muscle by Western blotting Using 12.5% polyacrylamide gel for SDS-PAGE, PGC1-alpha (4C1.3) Mouse monoclonal Ab (Calbiochem, Billerica ) Was diluted 1000-fold and GAPDH (14C10) Rabbit monoclonal Ab (Cell Signaling Technology) was diluted 10000-fold. Western blotting was performed in the same manner as in (2-5) above.
(2-7)ウエスタンブロッティングによる筋肉中のAktのリン酸化の解析
SDS−PAGEに12.5%ポリアクリルアミドゲルを用い、抗体として、phospho-Akt (Thr308) (244F9) Rabbit monoclonal Ab(Cell Signaling Technology)を2000倍希釈で、phospho-Akt (Ser473) Rabbit polyclonal Ab (Cell Signaling Technology)を2000倍希釈で、Akt Rabbit polyclonal Ab(Cell Signaling Technology)を4000倍希釈で、それぞれ用いたこと以外は、上記(2-5)と同様にウエスタンブロッティングを行った。(2-7) Analysis of phosphorylation of Akt in muscle by Western blotting Using 12.5% polyacrylamide gel for SDS-PAGE, phospho-Akt (Thr308) (244F9) Rabbit monoclonal Ab (Cell Signaling Technology) ) Was diluted 2000 times, phospho-Akt (Ser473) Rabbit polyclonal Ab (Cell Signaling Technology) was diluted 2000 times, and Akt Rabbit polyclonal Ab (Cell Signaling Technology) was diluted 4000 times. Western blotting was performed as in (2-5).
(2-8)ウエスタンブロッティングによる筋肉中のGSK3βのリン酸化の解析
SDS−PAGEに12.5%ポリアクリルアミドゲルを用い、抗体として、phospho-GSK3-beta (5B3) Rabbit monoclonal Ab(Cell Signaling Technology)を2000倍希釈で、GSK3-beta (27C10) Rabbit monoclonal Ab (Cell Signaling Technology)を4000倍希釈で、それぞれ用いたこと以外は、上記(2-5)と同様にウエスタンブロッティングを行った。(2-8) Analysis of phosphorylation of GSK3β in muscle by Western blotting Using 12.5% polyacrylamide gel for SDS-PAGE and using phospho-GSK3-beta (5B3) Rabbit monoclonal Ab (Cell Signaling Technology) as an antibody Western blotting was performed in the same manner as in (2-5) above except that GSK3-beta (27C10) Rabbit monoclonal Ab (Cell Signaling Technology) was used at a dilution of 4000 and diluted respectively.
(2-9)ウエスタンブロッティングによる筋肉中のFoxOファミリーのリン酸化の解析
SDS−PAGEに12.5%ポリアクリルアミドゲルを用い、抗体として、phospho-FoxO1 (Ser256) Rabbit polyclonal Ab(Cell Signaling Technology)を2000倍希釈で、FoxO1 (C29H4) Rabbit monoclonal Ab(Cell Signaling Technology)を5000倍希釈で、phospho-FoxO3a (Ser253) Rabbit polyclonal Ab(Cell Signaling Technology)を1000倍希釈で、FoxO3a (75D8) Rabbit monoclonal Ab(Cell Signaling Technology)を5000倍希釈で、phospho-FoxO4 (Ser193) Rabbit pAb(Cell Signaling Technology)を1000倍希釈で、FoxO4 (EPR5442) Rabbit mAb(Abcam)を1000倍希釈で、それぞれ用いたこと以外は、上記(2-5)と同様にウエスタンブロッティングを行った。(2-9) Analysis of FoxO family phosphorylation in muscle by Western blotting Using 12.5% polyacrylamide gel for SDS-PAGE, phospho-FoxO1 (Ser256) Rabbit polyclonal Ab (Cell Signaling Technology) as an antibody At 2000-fold dilution, FoxO1 (C29H4) Rabbit monoclonal Ab (Cell Signaling Technology) is diluted 5000-fold, phospho-FoxO3a (Ser253) Rabbit polyclonal Ab (Cell Signaling Technology) is diluted 1000-fold, FoxO3a (75D8) Rabbit monoclonal Ab (Cell Signaling Technology) diluted 5000 times, phospho-FoxO4 (Ser193) Rabbit pAb (Cell Signaling Technology) diluted 1000 times, FoxO4 (EPR5442) Rabbit mAb (Abcam) diluted 1000 times, respectively. Were subjected to Western blotting in the same manner as in (2-5) above.
(2-10)ウエスタンブロッティングによる筋肉中のMAFbxおよびMuRF1発現量の解析
抗体として、MAFbx (H-300) Rabbit polyclonal Ab(Santa Cruz)を1000倍希釈で、MuRF1 (H-145) Rabbit polyclonal Ab(Santa Cruz)を1000倍希釈で、GAPDH (14C10) Rabbit monoclonal Ab(Cell Signaling Technology)を10000倍希釈で、それぞれ用いたこと以外は、上記(2-5)と同様にウエスタンブロッティングを行った。(2-10) Analysis of MAFbx and MuRF1 expression levels in muscle by Western blotting As an antibody, MAFbx (H-300) Rabbit polyclonal Ab (Santa Cruz) was diluted 1000 times, and MuRF1 (H-145) Rabbit polyclonal Ab ( (Santa Cruz) was diluted 1000 times and GAPDH (14C10) Rabbit monoclonal Ab (Cell Signaling Technology) was diluted 10000 times, and Western blotting was performed in the same manner as in (2-5) above, except that each was used.
(3)結果
(3-1)体重
8週齢時の各群の平均体重と38週齢時の各群の平均体重の変化を図1に示した。SAMRの体重増加量と比較してSAMP8の体重増加量は著しく低かった。しかし、38週齢時において、SAMRおよびSAMP8ともに、牛車腎気丸群の方が普通食群より平均体重が重い傾向が認められたが、牛車腎気丸群と普通食群との間に有意差はなかった。
(3-2)食事摂取量
1週間の食事摂取量を測定し、各群の1日1匹当たりの食事摂取量を算出した。結果を図2に示した。SAMRとSAMP8との間に食事摂取量の差は認められなかった。また、SAMRおよびSAMP8ともに、牛車腎気丸群の方が普通食群より食事摂取量が少ない傾向が認められたが、牛車腎気丸群と普通食群との間に有意差はなかった。(3) Results (3-1) Body weight Changes in the average body weight of each group at the age of 8 weeks and the average body weight of each group at the age of 38 weeks are shown in FIG. The weight gain of SAMP8 was significantly lower than the weight gain of SAMR. However, at 38 weeks of age, both the SAMR and SAMP8 showed a tendency for the average weight to be heavier in the Ushazama Kigan test group than in the normal diet group. There was no difference.
(3-2) Food intake The food intake per week was measured, and the daily food intake per animal in each group was calculated. The results are shown in FIG. There was no difference in dietary intake between SAMR and SAMP8. In addition, in both the SAMR and the SAMP8, the ox cart kidney testicle group tended to have less food intake than the normal diet group, but there was no significant difference between the ox cart kidney test group and the regular diet group.
(3-3)ヒラメ筋のヘマトキシリン・エオジン染色像
ヒラメ筋のヘマトキシリン・エオジン染色像を図3に示した。上段のSAMR、下段SAMP8であり、左が普通食群、右が牛車腎気丸群である。左下のSAMP8普通食群のマウスのヒラメ筋は、上段のSAMRのヒラメ筋と比較して筋委縮の進行が認められた。一方、右下のSAMP8牛車腎気丸群のマウスのヒラメ筋は、筋委縮が明らかに改善していることが認められた。
(3-4)筋線維面積
各群のヒラメ筋の筋線維面積の測定結果を図4に示した。図中、*はP<0.0001で有意差があることを表す。図4から明らかなように、SAMP8普通食群は筋線維面積が顕著に減少していたが、SAMP8牛車腎気丸群は筋線維面積が普通食群より有意に大きく、SAMRと同等であることが示された。(3-3) Image of Soleus Muscle Stained with Hematoxylin and Eosin FIG. 3 shows an image of soleus muscle stained with hematoxylin and eosin. The upper part is SAMR and the lower part is SAMP8. The left side is the normal food group, and the right side is the ox cart kidney group. In the lower left SAMP8 normal diet group of the soleus muscle, the progression of muscle atrophy was observed as compared with the upper SAMR soleus muscle. On the other hand, it was confirmed that the muscle atrophy was clearly improved in the soleus muscle of the mouse in the lower right SAMP8 oxcart nephricle group.
(3-4) Muscle Fiber Area The measurement results of the muscle fiber area of the soleus muscle of each group are shown in FIG. In the figure, * indicates that there is a significant difference at P <0.0001. As is clear from FIG. 4, the muscle fiber area in the SAMP8 normal diet group was significantly reduced, but the SAMP8 oxcart nebula group had a significantly larger muscle fiber area than the normal diet group and was equivalent to SAMR. It has been shown.
(3-5)小括
SAMP8普通食群においてヒラメ筋の筋萎縮の進行が観察されたことから、従来老化促進モデルマウスとして使用されてきたSAMP8は、サルコペニアモデルマウスとして適切であることが明らかとなった。SAMP8牛車腎気丸群では、ヒラメ筋の筋萎縮が抑制されることが観察された。一方、SAMP8の普通食群と牛車腎気丸群の体重および食事摂取量に差がなかったことから、牛車腎気丸の薬効が直接的に筋肉の委縮を改善させたものと考えられた。すなわち、以上の結果から、牛車腎気丸投与に起因して食事摂取量が増加し、活動量が上がり、筋肉量が増加(体重が増加)した結果、筋萎縮が抑制されたのではないことが示された。(3-5) Summary Since the progression of soleus muscle atrophy was observed in the SAMP8 normal diet group, it was clear that SAMP8, which had been used as an aging promoting model mouse, was suitable as a sarcopenia model mouse. became. It was observed that in the SAMP8 oxcart nephricle group, muscle atrophy of the soleus was suppressed. On the other hand, since there was no difference in the body weight and dietary intake between the normal diet group of SAMP8 and the oxcart kidney testicle group, it was considered that the medicinal effect of oxcart kidney testicle directly improved muscle atrophy. That is, from the above results, it is not that muscle atrophy was suppressed as a result of increased dietary intake, increased activity, and increased muscle mass (weight gain) due to administration of Goshajinkigan It has been shown.
(3-6)遅筋(トロポニンI)および速筋(トロポニンT)の解析
サルコペニアでは速筋が減少し遅筋が増加することが知られている。そこで、免疫染色によりヒラメ筋標本の遅筋(トロポニンI陽性)および速筋(トロポニンT陽性)を染め分けた。結果を図5に示した。図中濃く染まっているのが遅筋、薄く染まっているのが速筋である。図5から明らかなように、SAMP8普通食群では遅筋の量が増加していたが、SAMP8牛車腎気丸群では遅筋の量が減少しており、SAMRと同等であった。
各群のマウスの筋肉中のトロポニンIおよびトロポニンTの発現量をウエスタンブロッティングで解析した結果を図6に示した。図6から明らかなように、SAMP8普通食群ではトロポニンIの発現量が増加し、トロポニンTの発現量が減少していたが、SAMP8牛車腎気丸群では普通食群よりトロポニンIの発現量が減少し、ロポニンTの発現量が増加していた。この結果は、上記の免疫染色の結果と一致した。(3-6) Analysis of slow muscle (troponin I) and fast muscle (troponin T) In sarcopenia, it is known that fast muscle decreases and slow muscle increases. Therefore, the slow muscle (troponin I positive) and fast muscle (troponin T positive) of the soleus muscle specimen were dyed separately by immunostaining. The results are shown in FIG. In the figure, the slow muscle is dyed darkly, and the fast muscle is dyed lightly. As is clear from FIG. 5, the amount of slow muscle was increased in the SAMP8 normal diet group, but the amount of slow muscle was decreased in the SAMP8 oxcart nephricle group, which was equivalent to SAMR.
The results of analyzing the expression levels of troponin I and troponin T in the muscle of each group of mice by Western blotting are shown in FIG. As is apparent from FIG. 6, the expression level of troponin I increased and the expression level of troponin T decreased in the SAMP8 normal diet group, but the expression level of troponin I in the SAMP8 oxcart nephrology group than in the normal food group. Decreased, and the expression level of loponin T was increased. This result was consistent with the above immunostaining results.
(3-7)筋肉中のPGC−1α発現量の解析
筋線維の強さは、生理範囲内におけるPGC−1α発現量に依存することが知られている(参考文献:Lin J et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibers. Nature. 2002 Aug 15;418(6899):797-801.)。そこで、各群のマウスの筋肉中のPGC−1αの発現量をウエスタンブロッティングで解析した。結果を図7に示した。図7から明らかなように、SAMP8普通食群ではPGC−1αの発現量が減少していたが、SAMP8牛車腎気丸群ではPGC−1αの発現量が増加しており、SAMRと同等であった。(3-7) Analysis of expression level of PGC-1α in muscle It is known that the strength of muscle fiber depends on the expression level of PGC-1α in the physiological range (reference: Lin J et al. Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibers. Nature. 2002 Aug 15; 418 (6899): 797-801.). Therefore, the expression level of PGC-1α in the muscle of each group of mice was analyzed by Western blotting. The results are shown in FIG. As is clear from FIG. 7, the expression level of PGC-1α was decreased in the SAMP8 normal diet group, but the expression level of PGC-1α was increased in the SAMP8 oxcart kidney testicle group, which was equivalent to SAMR. It was.
(3-8)筋肉中のAktのリン酸化の解析
セリン・スレオニンキナーゼであるAktは、Thr308およびSer473の2つのアミノ酸がリン酸化されることにより活性化され、このAktのシグナルが筋肉の量と質量を規定することが知れている(参考文献:Baumgartner RN et al.Predictors of skeletal muscle mass in elderly men and women.Mech Ageing Dev. 1999 Mar 1;107(2):123-36.、Roubenoff R, Hughes VA.Sarcopenia: current concepts.J Gerontol A Biol Sci Med Sci. 2000 Dec;55(12):M716-24.)。そこで、各群のマウスの筋肉中のAktのリン酸化をウエスタンブロッティングで解析した。結果を図8に示した。図8から明らかなように、SAMP8普通食群では、Aktの発現量は他の群と同等であるが、Thr308のリン酸化とSer473のリン酸化が減弱していた。一方、SAMP8牛車腎気丸群ではThr308およびSer473のリン酸化がSAMRと同等レベルに回復していた。(3-8) Analysis of phosphorylation of Akt in muscle Akt, a serine / threonine kinase, is activated by phosphorylation of two amino acids, Thr308 and Ser473, and this Akt signal is correlated with the amount of muscle. It is known to regulate mass (reference: Baumgartner RN et al. Predictors of skeletal muscle mass in elderly men and women. Mech Aging Dev. 1999 Mar 1; 107 (2): 123-36., Roubenoff R, Hughes VA. Sarcopenia: current concepts. J Gerontol A Biol Sci Med Sci. 2000 Dec; 55 (12): M716-24.). Therefore, phosphorylation of Akt in the muscle of each group of mice was analyzed by Western blotting. The results are shown in FIG. As is clear from FIG. 8, in the SAMP8 normal diet group, the expression level of Akt was the same as in the other groups, but phosphorylation of Thr308 and phosphorylation of Ser473 were attenuated. On the other hand, phosphorylation of Thr308 and Ser473 recovered to the same level as SAMR in the SAMP8 ox cart.
(3-9)筋肉中のGSK3βのリン酸化の解析
筋肉においては、Aktシグナルの下流に、グリコーゲン合成を促進するGSK3βが存在する。そこで、各群のマウスの筋肉中のGSK3βのリン酸化をウエスタンブロッティングで解析した。結果を図9に示した。図9から明らかなように、SAMP8普通食群では、GSK3βの発現量は他の群と同等であるが、Ser9のリン酸化が減弱していた。一方、SAMP8牛車腎気丸群ではSer9のリン酸化がSAMRと同等レベルに回復していた。(3-9) Analysis of phosphorylation of GSK3β in muscle In muscle, GSK3β that promotes glycogen synthesis exists downstream of the Akt signal. Therefore, the phosphorylation of GSK3β in the muscle of each group of mice was analyzed by Western blotting. The results are shown in FIG. As is clear from FIG. 9, in the SAMP8 normal diet group, the expression level of GSK3β was the same as in the other groups, but Ser9 phosphorylation was attenuated. On the other hand, Ser9 phosphorylation was restored to the same level as SAMR in the SAMP8 ox cart.
(3-10)PAS染色による筋肉中のグリコーゲン染色
各群のマウスのヒラメ筋の組織標本をPAS染色した結果を図10に示した。図中、濃く染まっているのがグリコーゲンである。図10から明らかなように、SAMP8普通食群ではグリコーゲンがほとんど染まっていないが、SAMP8牛車腎気丸群では劇的にグリコーゲン量が改善しており、加齢による筋肉のグリコーゲン貯蔵機能の低下が改善していることが示された。(3-10) Glycogen staining in muscle by PAS staining FIG. 10 shows the result of PAS staining of a tissue specimen of soleus muscle of each group of mice. In the figure, glycogen is darkly stained. As is apparent from FIG. 10, glycogen is hardly stained in the SAMP8 normal diet group, but the amount of glycogen is dramatically improved in the SAMP8 oxshakigan group, and the decrease in muscle glycogen storage function due to aging is evident. It was shown that it was improving.
(3-11)筋肉中のFoxOファミリーのリン酸化の解析
Aktシグナルのもう一つの下流にFoxOファミリーが存在する。Aktシグナルにより、FoxOファミリーのリン酸化が減弱されると、筋萎縮につながることが報告されている(参考文献:Machida S et al. Forkhead transcription factor FoxO1 transduces insulin-like growth factor's signal to p27Kip1 in primary skeletal muscle satellite cells. J Cell Physiol. 2003 Sep;196(3):523-31.、Kamei Y et al. Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch/red muscle) fiber genes, and impaired glycemic control. J Biol Chem. 2004 Sep 24;279(39):41114-23.)。そこで、各群のマウスの筋肉中のFoxOファミリーのリン酸化をウエスタンブロッティングで解析した。
結果を図11に示した。図11から明らかなように、SAMP8普通食群では、FoxO1のSer256およびFoxO3aSer253のリン酸化は、他の群とほぼ同等のレベルであったが、FoxO4のSer193のリン酸化が減弱していた。一方、SAMP8牛車腎気丸群ではSer193のリン酸化がSAMRと同等レベルに回復していた。(3-11) Analysis of phosphorylation of FoxO family in muscle FoxO family exists in the other downstream of Akt signal. It has been reported that when the phosphorylation of FoxO family is attenuated by Akt signal, it leads to muscle atrophy (reference: Machida S et al. Forkhead transcription factor FoxO1 transduces insulin-like growth factor's signal to p27Kip1 in primary skeletal J Cell Physiol. 2003 Sep; 196 (3): 523-31., Kamei Y et al. Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch / red muscle) fiber genes, and impaired glycemic control. J Biol Chem. 2004 Sep 24; 279 (39): 41114-23.). Thus, FoxO family phosphorylation in the muscle of each group of mice was analyzed by Western blotting.
The results are shown in FIG. As is clear from FIG. 11, phosphorylation of FoxO1 Ser256 and FoxO3aSer253 in the SAMP8 normal diet group was almost the same level as other groups, but phosphorylation of SerO of FoxO4 was attenuated. On the other hand, Ser193 phosphorylation was restored to the same level as SAMR in the SAMP8 ox cart.
(3-12)筋肉中のMAFbxおよびMuRF1発現量の解析
FoxOファミリーは、さらに下流のAtrogin−1/MAFbxとMuRF1を増加させ、筋萎縮を進行させると報告されている(参考文献:Clavel S et al.Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat Tibialis Anterior muscle. Mech Ageing Dev. 2006 Oct;127(10):794-801.、Bodine SC et al.Identification of ubiquitin ligases required for skeletal muscle atrophy.Science. 2001 Nov 23;294(5547):1704-8. Epub 2001 Oct 25.)。そこで、各群のマウスの筋肉中のMAFbxおよびMuRF1の発現量をウエスタンブロッティングで解析した。結果を図12に示した。図12から明らかなように、SAMP8普通食群ではMuRF1の発現量が増強されていたが、SAMP8牛車腎気丸群ではMuRF1の発現量が、SAMRと同等レベルに正常化されていた。(3-12) Analysis of expression levels of MAFbx and MuRF1 in muscle The FoxO family has been reported to further increase downstream Atrogin-1 / MAFbx and MuRF1 to promote muscle atrophy (Reference: Clavel Set et al. al.Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat Tibialis Anterior muscle.Mech Aging Dev. 2006 Oct; 127 (10): 794-801., Bodine SC et al.Identification of ubiquitin ligases required for skeletal muscle atrophy. Science. 2001 Nov 23; 294 (5547): 1704-8. Epub 2001 Oct 25.). Therefore, the expression levels of MAFbx and MuRF1 in the muscle of each group of mice were analyzed by Western blotting. The results are shown in FIG. As is clear from FIG. 12, the expression level of MuRF1 was enhanced in the SAMP8 normal diet group, whereas the expression level of MuRF1 was normalized to a level equivalent to that of SAMR in the SAMP8 oxcart.
(4)考察
以上より、牛車腎気丸に含まれるいずれかの成分が老化によるAktの細胞内シグナルの減弱を正常化し、その下流であるグリコーゲン合成に関わるGSK3βのリン酸化を改善する。同時に筋萎縮に関わるFoxOファミリーの中で、FoxO4のSer193のリン酸化を改善し、MuRF1の発現量を正常化し、サルコペニアを予防または治療できると考えられた。また、PGC−1α発現量を正常化することも、サルコペニアの予防または治療につながると考えられた。(4) Consideration As described above, any component contained in Goshajinkigan makes normal attenuation of Akt intracellular signal due to aging, and improves phosphorylation of GSK3β related to glycogen synthesis downstream thereof. At the same time, in the FoxO family involved in muscle atrophy, it was considered that the Ser193 phosphorylation of FoxO4 was improved, the expression level of MuRF1 was normalized, and sarcopenia could be prevented or treated. Moreover, normalizing the expression level of PGC-1α was considered to lead to the prevention or treatment of sarcopenia.
〔実施例2:老化促進モデルマウスのサルコペニア進行に対する漢方補腎剤の効果〕
(1)使用動物
老化促進モデルマウスであるSAMP8(7週齢、雄)および正常老化マウスであるSAMR(7週齢、雄)を日本エスエルシーから入手し、1週間の馴化後に試験に供した。動物は12時間明暗周期を持つ特定の病原体フリーの条件下で飼育した。[Example 2: Effect of Chinese herbal supplement on sarcopenia progression in senescence accelerated model mice]
(1) Animals used SAMP8 (7 weeks old, male), an aging-promoting model mouse, and SAMR (7 weeks old, male), a normal aging mouse were obtained from Japan SLC and subjected to the test after acclimation for 1 week. . Animals were raised under certain pathogen-free conditions with a 12 hour light / dark cycle.
(2)実験方法
実験プロトコールと飼育条件は大阪大学動物実験委員会によって承認され、「実験動物の管理と使用のための国立衛生研究所・ガイド」に従って、実験を実施した。
粉末飼料(MF、オリエンタル酵母工業株式会社)に4質量%の牛車腎気丸(乾地黄5.0 g, 山薬3.0 g, 山茱萸3.0 g, 茯苓3.0 g, 沢瀉3.0 g, 牡丹皮3.0 g,
桂皮1.0 g, 附子1.0 g, 牛膝3.0 g, 車前子3.0 g)、4質量%の八味丸(乾地黄5.0 g, 山薬3.0 g, 山茱萸3.0 g, 茯苓3.0 g, 沢瀉3.0 g, 牡丹皮3.0 g, 桂皮1.0 g, 附子1.0 g)または4質量%の六味丸(乾地黄5.0 g, 山薬3.0 g, 山茱萸3.0 g, 茯苓3.0 g, 沢瀉3.0 g, 牡丹皮3.0 g)を混ぜ、SAMP8に6週間摂取させた。対照として、粉末飼料に4質量%のバレイショデンプンを混ぜ、SAMRおよびSAMP8にそれぞれ6週間摂取させた。
サンプル採取および組織標本作製は、実施例1と同じ方法で行った。筋線維面積測定は、1標本当たり約100か所の領域を測定したこと以外、実施例1と同じ方法で行った。(2) Experimental method The experimental protocol and breeding conditions were approved by the Animal Research Committee of Osaka University, and the experiment was carried out according to the "National Institutes of Health Guide for the management and use of experimental animals".
Powdered feed (MF, Oriental Yeast Co., Ltd.) and 4% by weight Oxcart Nekimaru (dry ground yellow 5.0 g, mountain medicine 3.0 g, yam 3.0 g, salmon 3.0 g, saw rice 3.0 g, peony skin 3.0 g,
Cinnamon bark 1.0 g, appendix 1.0 g, cattle knee 3.0 g, car forehead 3.0 g), 4% by weight Hachimi-maru (dry land yellow 5.0 g, mountain medicine 3.0 g, yam 3.0 g, salmon 3.0 g, samurai 3.0 g, Peony skin 3.0 g, cinnamon bark 1.0 g, tsukemono 1.0 g) or 4% by weight of Rokumimaru (dry land yellow 5.0 g, mountain medicine 3.0 g, yam 3.0 g, strawberry 3.0 g, saw potato 3.0 g, peony skin 3.0 g) SAMP8 was ingested for 6 weeks. As a control, 4% by mass of potato starch was mixed with the powdered feed, and each was ingested by SAMR and SAMP8 for 6 weeks.
Sample collection and tissue preparation were performed in the same manner as in Example 1. The muscle fiber area was measured in the same manner as in Example 1 except that approximately 100 areas per sample were measured.
(3)結果
各群のマウスのヒラメ筋のヘマトキシリン・エオジン染色像を図13に示した。また、各群のヒラメ筋の筋線維面積の測定結果を図14に示した。図14中、*はP<0.05で有意差があることを表す。図13および図14から明らかなように、いずれの漢方補腎剤も老化促進モデルマウスのサルコペニア進行を抑制することが示された。抑制の程度は、牛車腎気丸>八味丸>六味丸であった。実施例1の結果と同様に、牛車腎気丸群の筋線維面積は、SAMRと同等であった。(3) Results Hematoxylin and eosin-stained images of the soleus muscle of each group of mice are shown in FIG. Moreover, the measurement result of the muscle fiber area of the soleus muscle of each group was shown in FIG. In FIG. 14, * indicates that there is a significant difference at P <0.05. As is clear from FIG. 13 and FIG. 14, it was shown that all Chinese herbal supplements suppress the progression of sarcopenia in senescence-accelerated model mice. The degree of suppression was Oxshaki Kikimaru>Hachimimaru> Rokumimaru. Similar to the results of Example 1, the muscle fiber area of the oxcart nephricle group was equivalent to SAMR.
〔実施例3:牛車腎気丸の抗サルコペニア効果の臨床的検討〕
(1)対象
大阪府内のクリニックにおいて2013年8月から12月までに、筋力低下を自覚し、牛車腎気丸内服を希望し、ロコモ度テストにボランティアとして協力した8名の患者を対象とした。[Example 3: Clinical study of anti-sarcopenia effect of oxcart nephrology]
(1) Subjects Targeting 8 patients who were aware of muscular weakness, hoped to be oxcart kidney kimaru, and cooperated as a volunteer for the locomotive degree test from August to December 2013 at a clinic in Osaka Prefecture. .
(2)方法
平成25年5月27日に公益社団法人日本整形外科学会ロコモチャレンジ!推進協議会が発表した「ロコモ度テスト」(将来ロコモティブシンドロームになり得る可能性を判定する方法)をベースに、以下の6項目の評価を行った。牛車腎気丸投与開始前に最初の評価を行い、外来受診の状況に応じて2〜3か月目に再評価を行った。牛車腎気丸投与開始前および牛車腎気丸治療後の各項目について平均値および標準偏差を算出し、paired t−testにより統計評価を行った。なお、ロコモチャレンジではロコモーショントレーニングを推奨しているが、今回は薬剤の効果を判定することが目的であるため、運動の指導は行わなかった。(2) Method The Japanese Orthopedic Association Locomo Challenge on May 27, 2013! Based on the “locomo degree test” announced by the Promotion Council (a method to determine the possibility of becoming a future locomotive syndrome), the following six items were evaluated. The first evaluation was performed before the start of the Oxcart nephrology administration, and re-evaluation was performed in 2 to 3 months depending on the situation of the outpatient visit. An average value and a standard deviation were calculated for each item before the start of oxcart kidney testicles and after treatment with oxcart kidney testicles, and statistical evaluation was performed by paired t-test. Locomo Challenge recommends Locomotion training, but this time the purpose was to determine the effect of the drug, so exercise guidance was not provided.
(3)評価項目
1.身長、体重、BMI
2.筋量、脂肪量(いずれもTANITA製マルチ周波数体組成計MC−980Aを用いて測定)
3.両手の握力測定
4.立ち上がりテスト(下肢筋力の強さを判定)
5.2ステップテスト(歩幅を図ることで歩行能力を判定)
6.ロコモ25(25の質問により身体状態、生活状況を評価する。身体における痛みや動かしにくさに加え、生活積極度についてもチェックし、運動器の身体状態と生活状態に不自由なことが生じる可能性を点数化し、将来ロコモになる危険度を判定する。)(3) Evaluation items Height, weight, BMI
2. Muscle mass and fat mass (both measured using a multi-frequency body composition meter MC-980A manufactured by TANITA)
3. 3. Measurement of grip strength of both hands Stand-up test (determines strength of lower limb muscle strength)
5.2 step test (walking ability is determined by stride)
6). Locomo 25 (Evaluate body condition and living situation by 25 questions. In addition to pain and inability to move in the body, check the degree of active life, and there may be inconvenience in the physical state and living state of the exercise equipment. (Determine the risk of becoming a locomotive in the future.)
「立ち上がりテスト」の方法は以下のとおりである。10、20、30および40cmの台を用意する。まず40cmの台に両腕を組んで腰かけ、両脚を肩幅くらいに広げ、床に対して脛がおよそ70度になるようにして、反動をつけずに立ち上がり、そのまま3秒間保持する。40cmの台から両脚で立ち上がれた場合、次に片脚でテストをする。初めの姿勢に戻り、左右どちらかの脚を上げ、反動をつけずに立ち上がり、3秒間保持できれば成功とする。左右ともに片脚で立ち上がることができれば成功とする。次に、10cmずつ低い台に移り、同様のテストを繰り返す。 The method of “rise test” is as follows. Prepare a 10, 20, 30 and 40 cm platform. First, sit down with your arms crossed on a 40 cm base, spread your legs to the shoulder width, stand up to the floor with the shin at approximately 70 degrees, and keep it standing for 3 seconds. If you get up on both legs from a 40cm stand, then test with one leg. Return to the initial position, raise either leg on the left, stand up without recoil, and hold for 3 seconds. If you can stand up with one leg on both the left and right, it will be a success. Next, move to a base 10 cm lower and repeat the same test.
「2ステップテスト」の方法は以下のとおりである。スタートラインを決め、両足のつま先を合わせ、できる限り大股で2歩歩き、両足を揃える。バランスをくずした場合は失敗とする。最初に立ったラインから、着地点のつま先までを測定する。2回行ってよかったほうの記録を採用する。以下の計算式で2ステップ値を算出する。
2ステップ値=2歩幅(cm)÷身長(cm)The method of “two-step test” is as follows. Determine the starting line, match the toes of both feet, walk as long as possible with two legs and align both feet. If the balance is lost, it will fail. Measure from the first standing line to the toe of the landing point. Adopt the record that was good to go twice. The 2-step value is calculated using the following formula.
2 step value = 2 steps (cm) ÷ height (cm)
(3)評価結果
(3-1)患者背景
患者背景を図15に示した。女性8人、各項目の平均値および標準偏差は、年齢62.3±10.3歳、身長159.0±5.6cm、体重54.6±7.3kg、BMI21.5±1.84、牛車腎気丸の平均投与期間は77.3±29.7日であった。(3) Evaluation results (3-1) Patient background The patient background is shown in FIG. Eight women, mean and standard deviation of each item are age 62.3 ± 10.3 years old, height 159.0 ± 5.6 cm, weight 54.6 ± 7.3 kg, BMI 21.5 ± 1.84, The average administration period of Goshajinkigan was 77.3 ± 29.7 days.
(3-2)開始時の評価
握力は、右が20.3±6.5kg、左が20.6±5.7kgであった。立ち上がりテストは、片足ができなかった患者が3人、40cmが可能であった患者が4人、10cmが1人であった。40〜60代の女性は、目安として40cmを片足で立ちあがれるとされていることから、対象患者は脚力がやや低下していると考えられた。2ステップ値は1.28±0.2であり、40〜60代の女性の平均値が1.45〜1.49であることから、対象患者は移動能力がやや低下していると考えられた。ロコモ25は10.3±10.8点であり、個人差が大きかった。(3-2) Evaluation at the start The grip strength on the right was 20.3 ± 6.5 kg and on the left was 20.6 ± 5.7 kg. In the standing-up test, there were 3 patients who could not have one leg, 4 patients who could be 40 cm, and 1 patient who was 10 cm. Since women in their 40s and 60s were supposed to stand 40cm on one leg as a guideline, it was considered that their target patients had slightly reduced leg strength. The 2-step value is 1.28 ± 0.2, and since the average value of women in their 40s and 60s is 1.45 to 1.49, it is considered that the target patient has a slightly reduced mobility. It was. Locomo 25 was 10.3 ± 10.8 points, and the individual difference was large.
(3-3)牛車腎気丸治療後の評価(全体)
図16に牛車腎気丸治療前後の体重、BMI、脂肪量、筋肉量の評価結果を示した。いずれの項目も有意な変化は認められなかった。
図17に牛車腎気丸治療前後の握力(左右)、2ステップ値、ロコモ25の評価結果を示した。右握力および2ステップ値の有意な改善が認められた。左握力も改善傾向が認められた。一方、ロコモ25については、明確な改善が認められなかった。(3-3) Evaluation after treatment of oxcart nephricle (total)
FIG. 16 shows the evaluation results of body weight, BMI, fat mass, and muscle mass before and after the treatment of Goshajinkigan. There was no significant change in any of the items.
FIG. 17 shows the evaluation results of grip strength (left and right), two step values, and locomo 25 before and after the treatment of the oxcart kidney testicles. Significant improvements in right grip strength and 2-step values were observed. The left grip strength also improved. On the other hand, no clear improvement was observed for Locomo 25.
(3-4)牛車腎気丸治療後の評価(著効例)
8例の対象患者中、著効を示した患者(第4症例、74歳女性)の評価結果について以下に説明する。この患者は、来院の2年前から甲状腺機能低下症としてチラージンの投与を受けていたが、甲状腺ホルモンは内服により問題ないにもかかわらず、筋肉痛が継続し改善しないため、漢方治療を希望して2013年10月31日に来院した。多発性筋炎などの膠原病の可能性を否定するために採血を行い、抗Jo−1抗体陰性であることを確認した。そこで、11月14日からツムラ牛車腎気丸エキス顆粒7.5gの内服を開始したところ、筋肉痛改善の自覚があったため内服を継続した。
図18に握力の推移を示した。図19に立ち上がりテストの推移を示した。図20に2ステップ値の推移を示した。図21にロコモ25の点数の推移を示した。図18から明らかなように、握力は右(13.1→18.5→24.2kg)、左(12.3→15.9→22.9kg)とも劇的な改善を示した。図19に示したように、投与開始前は不可能であった40cmの台から片足で立ち上がることが可能になった。2ステップ値は変化が認められなかったが(図20)、ロコモ25は順調な改善(23→18→14点)を示した(図21)。(3-4) Evaluation after treatment of oxcart nephricle (remarkable effect)
The evaluation results of the patients (fourth case, 74-year-old woman) who showed remarkable effects among the eight target patients will be described below. This patient had been treated with Tyrazine as hypothyroidism two years before the visit. However, although there was no problem with oral thyroid hormone, myalgia continued and did not improve. I visited the hospital on October 31, 2013. Blood was collected to deny the possibility of collagen disease such as polymyositis, and it was confirmed that the anti-Jo-1 antibody was negative. Then, on November 14, I started taking TSUMURA Beef Cart Kidney Extract Granule 7.5g, and continued to take it because I was aware of myalgia improvement.
FIG. 18 shows the transition of grip strength. FIG. 19 shows the transition of the rising test. FIG. 20 shows the transition of the 2-step value. FIG. 21 shows the change in the score of Locomo 25. As is clear from FIG. 18, the grip strength showed a dramatic improvement on both the right (13.1 → 18.5 → 24.2 kg) and the left (12.3 → 15.9 → 22.9 kg). As shown in FIG. 19, it was possible to stand up on one foot from a 40 cm base, which was impossible before the start of administration. Although the 2-step value did not change (FIG. 20), Locomo 25 showed a smooth improvement (23 → 18 → 14 points) (FIG. 21).
なお本発明は上述した各実施形態および実施例に限定されるものではなく、請求項に示した範囲で種々の変更が可能であり、異なる実施形態にそれぞれ開示された技術的手段を適宜組み合わせて得られる実施形態についても本発明の技術的範囲に含まれる。また、本明細書中に記載された学術文献および特許文献の全てが、本明細書中において参考として援用される。 The present invention is not limited to the above-described embodiments and examples, and various modifications are possible within the scope shown in the claims, and technical means disclosed in different embodiments are appropriately combined. The obtained embodiment is also included in the technical scope of the present invention. Moreover, all the academic literatures and patent literatures described in this specification are incorporated herein by reference.
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